ALBumin Italian Outcome Septic Shock-BALANCED Trial (ALBIOSS-BALANCED) (ALBIOSS-BAL)

Efficacy of Albumin Replacement and Balanced Solution in Patients with Septic Shock (the ALBIOSS-BALANCED Trial): a 2-by-2 Factorial, Investigator-initiated, Open- Label, Multicenter, Randomized, Controlled Trial

Septic shock is a devastating condition often observed in ICU. It is characterized by pro-inflammatory and immune responses, organ failures, high incidence of AKI and lethality. Fluid resuscitation is pivotal as supportive therapy. At present, there are no effective therapies to improve survival of such clinical condition, often characterized by a mortality as high as 40% during the first 90 days from diagnosis.

This project proposes a large 2-by-2 factorial randomized clinical trial testing the efficacy of albumin and the low- chloride balanced crystalloid solutions (either Ringer Lactate, Ringer Acetate, or Crystalsol - BAL) in septic shock.

The investigators have recently concluded a multicenter, randomized trial, the ALBIOS trial, in which, in a post-hoc analysis, albumin, in addition to crystalloids, reduced 90-day mortality in patients with septic shock, as compared to crystalloids alone (Caironi P et al, 2014). Crystalloids with supra-physiological chloride content may deteriorate renal perfusion, increasing the risk of acute kidney injury (AKI) and mortality.

Study Overview

• Status: Completed
• Conditions: Septic Shock
• Intervention / Treatment: Biological: Albumin; Other: Balanced

Detailed Description

The project will consist of a 2-by-2 factorial, investigator-initiated, open-label, multicenter, randomized, controlled trial, with PROBE design (Prospective Randomized Open Trial with Blinded Evaluation of Outcomes), in patients with septic shock, as defined according to clinical criteria.

Patients will be randomized in a 1:1:1:1 ratio to one of the 4 study groups (Albumin + BAL, Albumin + NS, BAL, NS).

Both the primary endpoints will include events evaluated objectively: 90-day mortality and incidence of AKI, as assessed by KDIGO criteria (KDIGO Acute Kidney Injury Work Group, 2012).

• Study Type: Interventional
• Enrollment (Actual): 1319
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Alessandria, Italy, 15121
    • Ospedale SS. Antonio e Biagio e Cesare Arrigo
  • Rimini, Italy, 47923
    • Ospedale infermi di Rimini
  • AN
    • Ancona, AN, Italy, 60126
      • Ospedali Riuniti di Ancona
  • BA
    • Bari, BA, Italy, 70124
      • Aou Policlinico di Bari
  • BG
    • Bergamo, BG, Italy, 24127
      • ASST Papa Giovanni XXIII
    • Seriate, BG, Italy, 24068
      • ASST BG Est - Ospedale Bolognini
    • Treviglio, BG, Italy, 24047
      • AST BG Ovest - PO Treviglio
  • BO
    • Bologna, BO, Italy, 40138
      • Policlinico Sant'Orsola-Malpighi
  • FE
    • Cona, FE, Italy, 44124
      • Azienda Ospedaliero - Universitaria di Ferrara - Arcispedale Sant'Anna
  • FI
    • Borgo San Lorenzo, FI, Italy, 50032
      • Ospedale del Mugello
    • Empoli, FI, Italy, 50053
      • Ospedale San Giuseppe
    • Firenze, FI, Italy, 50134
      • AOU Careggi
  • GR
    • Orbetello, GR, Italy, 58045
      • Ospedale Colline dell'Albegna
  • MB
    • Desio, MB, Italy, 20039
      • Presidio Ospedaliero di Desio
    • Monza, MB, Italy
      • Fondazione IRCCS San Gerardo dei Tintori
  • MI
    • Cinisello Balsamo, MI, Italy, 20092
      • ASST Nord Milano - Ospedale Bassini
    • Legnano, MI, Italy, 20025
      • ASST Ovest Milano
    • Milano, MI, Italy, 20162
      • ASST Grande Ospedale Metropolitano Niguarda
    • Milano, MI, Italy, 20122
      • Fondazione Irccs Ca' Granda - Ospedale Maggiore Policlinico
    • Milano, MI, Italy, 20157
      • ASST Fatebenefratelli - Sacco P.O. Sacco
    • San Donato Milanese, MI, Italy, 20097
      • IRCCS Policlinico San Donato
  • MO
    • Modena, MO, Italy, 41125
      • Azienda Ospedaliero-Universitaria di Modena, Policlinico di Modena
  • PA
    • Palermo, PA, Italy, 90127
      • AOU Policlinico Paolo Giaccone
    • Palermo, PA, Italy, 90127
      • ISMETT
  • PI
    • Pisa, PI, Italy, 56126
      • AOU Pisana
  • PN
    • Pordenone, PN, Italy, 33170
      • As FO Azienda sanitaria Friuli Occidentale
  • PV
    • Pavia, PV, Italy, 27100
      • Fondazione IRCCS Policlinico San Matteo
  • RE
    • Reggio Emilia, RE, Italy, 43123
      • IRCCS ASMN Reggio Emilia
  • RM
    • Roma, RM, Italy, 00168
      • Fondazione Policlinico Universitario A. Gemelli, Università Cattolica del Sacro Cuore
  • TN
    • Trento, TN, Italy, 38122
      • Ospedale Santa Chiara
  • TO
    • Moncalieri, TO, Italy, 10024
      • Ospedale Santa Croce
    • Orbassano, TO, Italy, 10043
      • Azienda Ospedaliero - Universitaria S. Luigi Gonzaga
    • Torino, TO, Italy, 10126
      • AOU Città della Salute e della Scienza di Torino
  • TS
    • Trieste, TS, Italy, 34128
      • ASU Giuliano Isontina
  • UD
    • Udine, UD, Italy, 33100
      • Azienda Sanitaria Universitaria Integrata di Udine
  • VA
    • Varese, VA, Italy, 21100
      • Ospedale di Circolo e Fondazione Macchi
  • VR
    • Verona, VR, Italy, 37126
      • Azienda Ospedaliera Universitaria Integrata di Verona

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 96 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Patients with septic shock if they meet the two following criteria:

1. Presence of an infection (known or suspected) in at least one site:

   1. Lung
   2. Abdomen
   3. Urinary tract
   4. Others (blood, skin and soft tissues, central nervous system, bones and joints, cardiac system, reproductive organs).
2. Presence of a severe and acute, sepsis-related cardiovascular failure (as assessed by the SOFA score - see Annex 1), requiring vasopressor to maintain mean arterial pressure >=65 mmHg, despite adequate volume resuscitation a) Cardiovascular SOFA score > 2 (3 or 4) If the patient is unable to provide informed consent, she/he can be included in the trial provided that the requirements of ongoing laws are fulfilled; details on this approach are provided in the protocol, par 11.1 and related Annex 3. The patient will be informed about having been included in a clinical trial, as soon as she/he will regain consciousness.

Exclusion Criteria:

1. Age < 18 years
2. Moribund state
3. Known or suspected adverse reaction to albumin administration
4. Septic shock in patients with traumatic brain injury or a clinically active cerebral lesion (known or suspected)
5. Severe congestive heart failure (NYHA III and IV classes)
6. Clinical situations in which the use of albumin is known or supposed to be clinically beneficial (hepatic cirrhosis with ascites, malabsorption syndrome or protein-losing enteropathy, nephrotic syndrome, burns)
7. More than 24 hours after the onset of septic shock
8. Religious objection to the administration of human blood products
9. Presence of chronic end-stage renal disease
10. Severe hyperkalemia (> 6 mmol/L)
11. Known or suspected pregnancy based on patient information
12. Enrollment in other experimental interventional studies
13. Laboratory confirmation for SARS-CoV-2 infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Albumin + Balanced; Human Albumin In parallel with fluid administration for volume resuscitation, patients will receive 400 ml of 20% albumin solution both at randomization (D0) and at day 1 (D1). Subsequently, from day 2 (D2) until day 90 (D90) or ICU discharge (whichever comes first), 20% albumin will be administered on a daily basis, to maintain serum albumin concentration equal to or greater than 30 g/L, based upon serum albumin determination. Balanced crystalloid solutions According to the preference and the standard use of the participating center: Ringer Lactate; Ringer Acetate; Crystalsol	Biological: Albumin; Human Albumin In parallel with fluid administration for volume resuscitation, patients will receive 400 ml of 20% albumin solution both at randomization (D0) and at day 1 (D1). Subsequently, from day 2 (D2) until day 90 (D90) or ICU discharge (whichever comes first), 20% albumin will be administered on a daily basis, to maintain serum albumin concentration equal to or greater than 30 g/L, based upon serum albumin determination.; Other: Balanced; Balanced crystalloid solutions are traditionally crystalloid solutions containing a relatively low concentration of chloride as compared to 0.9% NaCl containing solutions (Normal Saline).; Other Names: Ringer Lactate, Ringer Acetate, Crystalsol
Experimental: Albumin + Saline; Human Albumin In parallel with fluid administration for volume resuscitation, patients will receive 400 ml of 20% albumin solution both at randomization (D0) and at day 1 (D1). Subsequently, from day 2 (D2) until day 90 (D90) or ICU discharge (whichever comes first), 20% albumin will be administered on a daily basis, to maintain serum albumin concentration equal to or greater than 30 g/L, based upon serum albumin determination. Normal Saline Na+ 154 mEq/L, Cl- 154 mEq/L (0.9% NaCl).	Biological: Albumin; Human Albumin In parallel with fluid administration for volume resuscitation, patients will receive 400 ml of 20% albumin solution both at randomization (D0) and at day 1 (D1). Subsequently, from day 2 (D2) until day 90 (D90) or ICU discharge (whichever comes first), 20% albumin will be administered on a daily basis, to maintain serum albumin concentration equal to or greater than 30 g/L, based upon serum albumin determination.
Experimental: Balanced; Balanced crystalloid solutions (Ringer Lactate, Ringer Acetate, Crystalsol)	Other: Balanced; Balanced crystalloid solutions are traditionally crystalloid solutions containing a relatively low concentration of chloride as compared to 0.9% NaCl containing solutions (Normal Saline).; Other Names: Ringer Lactate, Ringer Acetate, Crystalsol
No Intervention: Saline; Normal Saline Na+ 154 mEq/L, Cl- 154 mEq/L (0.9% NaCl).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause 90-day mortality	All-cause death from randomization to 90 days	Up to 90 days
Combined co-primary endpoint	The composite of all-cause death from randomization to 90 days and new occurrence of acute kidney injury (AKI).	Up to 90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ICU mortality	All-cause death occurring in Intensive Care Unit (ICU)	Up to ICU discharge, a median of 9 days
In-hospital mortality	All-cause death occurring during hospital stay	Up to hospital discharge, a median of 20 days
1-year mortality	All-cause death from randomization to 1 year	Up to 1 year
SOFA score	Severity and incidence of organ failures, as assessed by the Sequential Organ Failure Assessment (SOFA) score. SOFA score is used to determine the extent of organ function in a patient while in the intensive care unit. The score is based on 6 different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems. The scale of each score ranges from 0 (no dysfunction) to 4 (maximal dysfunction). The 6 scores are then added up to provide a global score: the highest the value, the worst the condition of the patient.	Up to 90 days or ICU discharge - a median of 9 days - whichever comes first
RRT	First use of Renal Replacement Therapy (RRT) during ICU stay	Up to 90 days or ICU discharge - a median of 9 days - whichever comes first
Need for vasopressors	Duration of the need for vasopressors during ICU stay	Up to 90 days or ICU discharge - a median of 9 days - whichever comes first
Mechanical ventilation	Duration of mechanical ventilation during ICU stay	Up to 90 days or ICU discharge - a median of 9 days - whichever comes first
Secondary infections in ICU	Incidence of secondary-acquired infections during ICU stay	Up to 90 days or ICU discharge - a median of 9 days - whichever comes first
Duration of stay in ICU	Duration expressed as number of days spent in ICU	Up to ICU discharge, a median of 9 days
Duration of stay in hospital	Duration expressed as number of days spent in hospital	Up to hospital discharge, a median of 20 days
Incidence of AKI during ICU stay	Assessed by the Kidney Disease Improving Global Outcome (KDIGO) criteria as any of the following: (1) increase in serum creatinine >=0.3 mg/dl (26.5 mmol/l) within 48 hours; or (2) increase in SCr to >=1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or (3) urine volume <0.5 ml/kg/h for 6 hours.	Up to 90 days or ICU discharge - a median of 9 days - whichever comes first
1-year functional and physical disability	Evaluation by specific psyco-functional tests	Up to 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severe metabolic acidosis	Incidence of severe metabolic acidosis	Up to 90 days or ICU discharge - a median of 9 days - whichever comes first
Severe hyperkalemia	Incidence of severe hyperkalemia	Up to 90 days or ICU discharge - a median of 9 days - whichever comes first

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
• Collaborators: Istituto Di Ricerche Farmacologiche Mario Negri
• Investigators: Principal Investigator: Pietro Caironi, MD, AOU S. Luigi Gonzaga, Orbassano; Principal Investigator: Giacomo Grasselli, MD, Policlinico di Milano Ospedale Maggiore | Fondazione IRCCS Ca' Granda

Publications and helpful links

General Publications

• Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013 Aug 29;369(9):840-51. doi: 10.1056/NEJMra1208623. No abstract available. Erratum In: N Engl J Med. 2013 Nov 21;369(21):2069.
• SAFE Study Investigators; Finfer S, McEvoy S, Bellomo R, McArthur C, Myburgh J, Norton R. Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis. Intensive Care Med. 2011 Jan;37(1):86-96. doi: 10.1007/s00134-010-2039-6. Epub 2010 Oct 6.
• Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, Fanizza C, Caspani L, Faenza S, Grasselli G, Iapichino G, Antonelli M, Parrini V, Fiore G, Latini R, Gattinoni L; ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014 Apr 10;370(15):1412-21. doi: 10.1056/NEJMoa1305727. Epub 2014 Mar 18.
• Mehlman DJ, Bulkley BH, Wiernik PH. Serum alpha-1-fetoglobulin with gastric and prostatic carcinomas. N Engl J Med. 1971 Nov 4;285(19):1060-1. doi: 10.1056/NEJM197111042851907. No abstract available.
• Semler MW, Self WH, Rice TW. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018 May 17;378(20):1951. doi: 10.1056/NEJMc1804294.

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2019
• Primary Completion (Actual): October 31, 2024
• Study Completion (Actual): January 31, 2025

Study Registration Dates

• First Submitted: August 3, 2018
• First Submitted That Met QC Criteria: August 29, 2018
• First Posted (Actual): August 31, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 28, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Septic Shock; Albumin; Balanced crystalloids
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Shock, Septic
• Other Study ID Numbers: RF-2016-02361583

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No